Molecular Markers Of The Progression Of Intestinal Metaplasia To Gastric Cancer
Funder
National Health and Medical Research Council
Funding Amount
$556,618.00
Summary
Gastric cancer (GC) is the second most common cause of cancer-related death globally. It is a surgically treatable disease that has good prognosis if detected at an early stage. The majority of patients in our community are detected at a late stage, where less than 20% of patients survive 5 years. The majority of GC is preceded by distinct histological stages that follow a progression from gastric mucosal inflammation, intestinal metaplasia (IM) and eventually cancer. These stages are characteri ....Gastric cancer (GC) is the second most common cause of cancer-related death globally. It is a surgically treatable disease that has good prognosis if detected at an early stage. The majority of patients in our community are detected at a late stage, where less than 20% of patients survive 5 years. The majority of GC is preceded by distinct histological stages that follow a progression from gastric mucosal inflammation, intestinal metaplasia (IM) and eventually cancer. These stages are characterised by genetic events that are largely unknown and occur over a period that can take years. It is also evident, especially in countries where GC is not as prevalent, that only a proportion of individuals will eventually develop GC. The long latency from the develpoment of IM and diagnosis of GC offers an opportunity to intervene and study the changes that lead to GC as well as find genes that may predict which individuals will progress. IM is the stage in which intervention is obvious. It is very easily diagnosed, is present for a long time and, for certain individuals, will eventually accumulate enough genetic events that will mandate progression to GC. Targeted screening of these individuals will enable a feasible strategy to find early GC, and avoid costly non-targeted screening. This proposal seeks to find key genetic events responsible for the transition of IM to GC. The first step utilises Affymetrix arrays to detect genes expressed in IM and specifically linked to GC. These candidates will be validated and used to study their role in the progression to GC using a mouse model of GC. This study is designed to find genes responsible for GC that can be used as: 1) a marker of progression in humans that will be used as a tool to stratify individuals into a screening protocol; 2) candidates to be tested in animal studies to study the pathogenesis of GC and potentially used as preventative or therapeutic targets.Read moreRead less
In Vivo Models For Understanding The Cellular And Molecular Pathogenesis Of Barrett's Oesophagus
Funder
National Health and Medical Research Council
Funding Amount
$283,767.00
Summary
The incidence of oesophageal adenocarcinoma, a malignancy that is almost invariably fatal, has doubled in recent years and continues to increase at an alarming rate. Oesophageal adenocarcinoma arises from Barrett's oesophagus, a premalignant condition that effects up to 2% of the population. In Barrett's, the normal cells of the oesophageal lining are changed to become more like cells that line the intestine. We have developed novel 3-dimensional cell culture models that allow us to reproduce th ....The incidence of oesophageal adenocarcinoma, a malignancy that is almost invariably fatal, has doubled in recent years and continues to increase at an alarming rate. Oesophageal adenocarcinoma arises from Barrett's oesophagus, a premalignant condition that effects up to 2% of the population. In Barrett's, the normal cells of the oesophageal lining are changed to become more like cells that line the intestine. We have developed novel 3-dimensional cell culture models that allow us to reproduce the normal layered structure of the human oesophageal lining in the laboratory and we propose to use these models to address key issues in the biology of Barrett's oesophagus. In aim 1, we wish to determine if the cells in patients with Barrett's have been permanently, or only transiently, altered and to understand the role of gastric acid- bile and accessory cells in this transformation. In aim 2 we will look more closely at the molecular changes that drive the cellular transformation characteristic of Barrett's. We will do this by manipulating the expression of selected genes in human oesophageal cells and assessing the effects of these genes on cell growth and differentiation using our cell culture models. The results of these studies will pave the way for the design of appropriate clinical strategies to treat Barrett's oesophagus and prevent the progression of this premalignant condition to oesophageal adenocarcinoma.Read moreRead less
Barrett's oesophagus (BO) is a condition that arises in some patients with chronic reflux (heartburn) and increases the risk of developing cancer of the oesophagus. However, the exact mechanisms involved in its development are unknown. This project aims to investigate how a protein called sonic hedgehog might be involved using novel cell culturing techniques that allow us to model the growth of oesophageal tissue in the laboratory. This could lead to development of new therapies for treating BO.
Spatio-temporal Analysis Of Rat Intestinal Motility In Physiological And Disease Models
Funder
National Health and Medical Research Council
Funding Amount
$358,750.00
Summary
This project addresses the question of how the movements of the gut are controlled in health and disease. The progress of food along the gut is due to movements of the involuntary muscle of the wall of the intestine. Three fundamental mechanisms are involved. One is the spontaneous ability of the intestinal muscle to contract rhythmically and is driven by a delicate net of pacemaker cells. Fast propulsion of food contents depends on nerve circuits in the gut wall that generate a powerful pumping ....This project addresses the question of how the movements of the gut are controlled in health and disease. The progress of food along the gut is due to movements of the involuntary muscle of the wall of the intestine. Three fundamental mechanisms are involved. One is the spontaneous ability of the intestinal muscle to contract rhythmically and is driven by a delicate net of pacemaker cells. Fast propulsion of food contents depends on nerve circuits in the gut wall that generate a powerful pumping behaviour to prevent over-filling or to eject toxic or irritating substances (eg: some laxatives activate this mechanisms). This is often called peristalsis. A third mechanism consists of activity of nerve cells in the gut, that slowly propagates along the intestine and causes the muscle to contract, sweeping along any remnants. The movements generated by these three mechanisms occur in segments of intestine isolated from rats. The major difficulty up until now has been to relate the actual movements in living animals to these fundamental mechanisms. It is now possible to bridge this gap because we have developed methods to record, display and measure graphically the actual movements. Movements are transformed into spatio-temporal maps which show all of the contractions over a period of time. Coordinated activity is visible in these maps as recognisable patterns or visual objects. Measurements can be readily made with conventional statistics. The literature in gastroenterology is full of descriptions of motility based on indirect methods of recordings. In this project we will be able to correlate the previous indirect methods with the new graphic methods and thus establish a clearer, simpler and more accurate classification of normal patterns of intestinal motility. We will then use this to establish what goes wrong in a number of experimental diseases known to affect adversely the movements of the intestine.Read moreRead less
Effects Of Ischemia/ Reperfusion Injury On Enteric Neurons And Neuroprotective Strategies
Funder
National Health and Medical Research Council
Funding Amount
$566,277.00
Summary
The intestine can suffer restricted blood flow, creating a region of damaged or dead bowel. This leads to severe medical emergencies, complications and even death. Loss of blood flow and damage can be a serious complication for intestinal transplant surgery, which compromises patient survival and recovery. The project brings together transplant surgeons and basic scientists to solve problems caused by intestinal ischemia. A major result will be to improve outcomes for Australian patients
The Role Of Transferrin Receptor, Divalent Metal Transporter, Ferroportin And Hemochromatosis Protein In Iron Absorption
Funder
National Health and Medical Research Council
Funding Amount
$195,990.00
Summary
Within Australia 1 in 300 people of Caucasian origin have a genetic defect which makes them absorb more iron from the diet than they need. Excess iron is a major problem because it damages cells and this is most obvious in the pancreas where the cells make insulin are destroyed and diabetes mellitus develop. In the liver cirrhosis and cancer often occur. Iron also accumulates in other tissues such as the heart and joints resulting in damage to these organs. The genetic defect has recently been i ....Within Australia 1 in 300 people of Caucasian origin have a genetic defect which makes them absorb more iron from the diet than they need. Excess iron is a major problem because it damages cells and this is most obvious in the pancreas where the cells make insulin are destroyed and diabetes mellitus develop. In the liver cirrhosis and cancer often occur. Iron also accumulates in other tissues such as the heart and joints resulting in damage to these organs. The genetic defect has recently been identified but how the defective protein causes the cells of the intestine to absorb more iron into the body than is needed remains unknown. This has led to the idea that the normal protein is responsible for controlling the amount of iron absorbed. Recent studies have shown a link between this protein and another called transferrin receptor. These two molecules are thought to co-operate in determining how much iron will be absorbed. Once this is determined other molecules called iron transporters are produced and these are responsible for moving the iron from the intestine into the blood. When not much iron is required only a small number of transporters are made and when more iron is required then many more are produced. How these transporters program the level of iron absorption is unknown but the process probably involves the transferrin receptor and the hemochromatosis protein. This project will investigate the function of the molecules that determine the programe for how much iron is to be absorbed, and secondly how this is linked to the production and movement of the transproters that co-ordinate this function.Read moreRead less